Metabolism of phenylalanine & tyrosine

Metabolism of phenylalanine & tyrosine

Objective

•       At the end of this lecture, student will be able to

–      Explain the metabolism of phenylalanine & tyrosine and their metabolic disorders

Metabolism of phenylalanine & tyrosine

•       Phenylalanine and tyrosine are structurally related aromatic amino acids

•       Phenylalanine is an essential amino acid while tyrosine is non-essential

•       Besides its incorporation into proteins, the only function of phenyl alanine is its conversion to tyrosine

•       For this reason, ingestion of tyrosine can reduce the dietary requirement of phenylalanine

•       This phenomenon is referred to as 'sparing action' of  tyrosine on phenylalanine

Biosynthesis (conversion of Phenylalanine and Tyrosine)

•       Degradation of phenylalanine mostly occurs through tyrosine

•       Phenylalanine is hydroxylated at para-position by phenylalanine hydroxylase to produce tyrosine( p-hydroxyphenylalanine)

•       This is an irreversible reaction and  require phenylalanine hydroxylase and specific coenzyme biopterin, which is structurally related to folate

•       The active form of biopterin is tetrahydrobiopterin

•       In the phenylalanine hydroxylase reaction, tetrahydrobiopterin is oxidized to dihydrobiopterin

•       Tetrahydrobiopterin is regenerated by NADPH-dependent dihydrobiopterin reductase

•       The enzyme phenylalanine hydroxylase (liver) convert phenylalanine to tyrosine, the reaction involves the incorporation of one atom of molecular oxygen (O₂) into the para position of phenylalanine while the other atom of O₂ is reduced to form water

•       Tetrahydrobiopterin that supplies the reducing equivalents which, in turn, are provided by NADPH

•       Defect in phenylalanine hydroxylase leads to phenylketonuria (PKU)

DISORDERS OF TYROSINE (PHENYLALANINE) METABOLISM

•       Phenylketonuria: Defective phenylalanine hydroxylase

•       Tyrosinemia type II: Defective Tyrosine transaminase

•       Neonatal tyrosinemia: Defective p-hydroxyphenyl pyruvate dioxygenase (Tyrosinemia type III)

•       Alkaptonuria: defective homogentisate oxidase

•       Tyrosinemia type I: Defective fumarylacetoacetate hydroxylase and/or maleyl acetoacetate isomerase

•       Albinism: Defective tyrosinase

Metabolic disorders

Phenylketonuria (PKU)

•       Deficiency of phenylalanine hydroxylase – classical

•       New variant – due to deficiency of dihydrobiopterin reductase

•       Mental retardation

•       Effect on pigmentation

•       Treatment- Dietary approach

Tyrosinemia type II:

•       Very rare

•       Herpetiformic keratitis

•       Palmoplanter hyperkeratosis with ulcers

•       PMR, growth retardation

•       Dietary treatment

•       Richner-Hanhart syndrome

•       Defective enzyme: tyrosine transaminase

•       Accumulation of tyrosine and its metabolites

•       Skin (dermatitis) and eye lesions

•       Mental retardation

Neonatal Tyrosinemia

•       Absence of p-hydroxyl phenyl pyruvate dioxygenase

•       Well responded to ascorbic acid therapy

Tyrosinemia type 1

•       Deficiency of fumarylacetoacetyl hydroxylase and/or maleylacetoacetyl isomerase

•       Causes:

•       Liver failure

•       Poly neuropathy

•       Rickets

•       Renal tubular dysfunction

Alkaptonuria

•       Deficiency of Homogentisate oxidase

Albinism

•       Lack of synthesis of pigment melanin

•       Defect in tyrosinase-enzyme responsible for synthesis of melanin

•       Deficiency or lack of the enzyme tyrosinase.

•       Decrease in melanosomes of melanocytes.

•       Impairment in melanin polymerization.

•       Lack of protein matrix in melanosomes.

•       Limitation of substrate (tyrosine) availability.

•       Presence of inhibitors of tyrosinase.

Summary

•       Children with Alkaptonuria are asymptomatic, besides producing brown or black urine

•       Treatment for classic PKU is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients